Airway mucus hypersecretion has been linked to several of the pathological features of respiratory diseases such as asthma [Aikawa et al, 1992], chronic obstructive pulmonary disease (COPD) [Vestbo, 2002] and cystic fibrosis (CF) [Boucher, 2002]. Indeed, mucus hypersecretion has been linked to an increase in frequency and duration of infection, decline in lung function and increase in morbidity and mortality in respiratory diseases [Vestbo, 2002; Prescott et al, 1995; Vestbo et al, 1996]. Whilst in the large airways mucus is produced by goblet cells and submucosal glands, in the small airways the only source of mucus is the goblet cell [Rogers, 2003]. The mucins MUC5AC and MUC5B are major components of airway mucus secretions in respiratory diseases such as asthma, COPD and CF [Williams et al, 2006; Rose and Voynow, 2006; Rogers, 2003]. Mucus hypersecretion is a feature of asthma where morphometric analysis of lungs from patients who died from a severe acute asthma attack showed increases in goblet cell numbers and mucus in the airway lumen [Aikawa et al, 1992]. Mucus plugging of the airway lumen has been reported as a major contributing cause to fatal asthma in most patients [Kuyper et al, 2003; Hays and Fahay, 2003]. MUC5AC expression is increased in status asthmaticus compared to normal individuals and is localized to the surface epithelium, lumen and goblet cells [Gronenberg et al, 2002a]. Increased numbers of goblet cells have also been reported in subjects with mild to moderate asthma compared to healthy individuals and levels of secreted mucin are reported to be higher in the airways of patients with moderate asthma [Ordonez et al, 2001]. Additionally, increased MUC5AC mucin staining of goblet cells of subjects with asthma compared to healthy individuals has bee reported [Ordonez et al, 2001]. The mucin MUC5B is also produced by some airway surface goblet cells in asthmatics [Gronenberg et al, 2002a]. The progression of COPD has been reported to be strongly associated with accumulation of mucus in the lumen of the small airways [Hogg et al, 2004]. In individuals with COPD increased expression of MUC5AC has been described within the bronchiolar epithelium in addition to increased levels of MUC5B within the bronchiolar lumen [Caramori et al, 2004]. MUC5B has also been reported as a major mucin in sputum of patients with COPD in a separate study [Kirkham et al, 2002]. The increased mucus observed in the lumen of bronchioles in COPD patients has been suggested to contribute to obstruction of the peripheral airways in COPD [Caramori et al, 2004]. Increased numbers of goblet cells in the bronchiolar epithelium of patients with COPD and chronic bronchitis have also been described [Saetta et al, 2000]. In CF mucus hypersecretion is associated with airflow obstruction and, in fatal cases, occlusion of the small airways [Williams et al, 2006]. Excessive mucus also appears to contribute to CF morbidity by increasing the frequency and severity of pulmonary infections [Williams et al, 2006]. Although concentrations of secreted mucins MUC5AC and MUC5B have been reported to be decreased in CF subjects compared with normals [Henke et al, 2004], MUC5AC and MUC5B are increased in sputum of CF patients during exacerbations [Henke et al, 2007]. Goblet cell hyperplasia resulting from increased numbers of MUC5AC-positive cells, have been reported to be increased in cystic fibrosis lung [Gronenberg et al, 2002b].
Whilst IL-13 has been shown to influence MUC5AC gene and protein expression in vitro and in vivo [Wills-Karp et al, 1998; Zhu et al, 1999; Kuperman et al, 2002; Atherton, Jones and Danahay, 2003], it has no effect on the mucin MUC5B. The mediators of MUC5B production are not well characterized.
Neuregulins are signalling proteins that mediate multiple cell-cell interactions via the receptor tyrosine kinases of the ERB family. At least 15 different isoforms of Neuregulin-1 (NRG1) exist as a result alternative splicing [Falls, 2003]. Two of these isoforms, NRG1a and NRG1β1, differ in the C-terminal portion of the EGF-like domain [Holmes et al, 1992]. NRG1 is thought to bind to ErbB3 or ERRB4 which form heterodimers with ErbB2 [Falls, 2003]. NRG1β1 binds to ErbB3 with 100-fold higher affinity than NRG1a. NRG1β1 also has a 100-fold greater affinity for the ErbB2/ErbB3 heterodimer than ErbB3 homodimers [Jones et al, 1999]. ErbB3 lacks tyrosine kinase activity, but dimerisation with ErbB2 results in the formation of an active heterodimer which can mediate downstream signals [Citri, Skaria and Yarden, 2003]. A role for NRG1 and the ErbB2 and 3 receptors in human lung development have previously been suggested through immunohistochemical and functional studies on fetal lung tissue [Patel et al, 2000]. NRG1β1 is secreted from fetal lung fibroblasts and stimulates type II cell surfactant synthesis and is therefore proposed to control fetal lung maturation through mesenchymal-epithelial interactions [Dammam et al, 2003]. More recently the NRG 1a isoform has been suggested to play a role in epithelial wound repair and remodeling in the airways [Vermeer et al, 2003]. In this study the ErbB2 receptor was shown to been expressed on the basolateral surface of differentiated epithelial cells and NRG1a ligand expressed at the apical surface. Consequently ligand receptor interactions are not thought to take place until an epithelial injury has occurred. Expression of NRG (sometimes referred to as Heuregulin, “HRG”) has been examined in bronchial tissue from COPD patients and higher expression observed in intact epithelium of subjects with COPD compared to those without COPD [de Boer et al, 2006]. However, in the study of de Boer et al. the specific isoform of NRG1 investigated was not stated.
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